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Sodium phenylbutyrate reduces repetitive self-grooming behavior and rescues social and cognitive deficits in mouse models of autism

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Abstract

Autism spectrum disorder (ASD) is a neurodevelopment disorder characterized by deficits in social interaction and restrictive, repetitive, and stereotypical patterns of behavior. However, there is no pharmacological drug that is currently used to target these core ASD symptoms. Sodium phenylbutyrate (NaPB) is a well-known long-term treatment of urea cycle disorders in children. In this study, we assessed the therapeutic effects of NaPB, which is a chemical chaperone as well as histone deacetylase inhibitor on a BTBR T + Itpr3tf/J (BTBR) mice model of ASD. We found that acute and chronic treatment of NaPB remarkably improved, not only core ASD symptoms, including repetitive behaviors and sociability deficit, but also cognitive impairment in the BTBR mice. NaPB substantially induced histone acetylation in the brain of the BTBR mice. Intriguingly, the therapeutic effects of NaPB on autistic-like behaviors, such as repetitive behaviors, impaired sociability, and cognitive deficit also showed in the valproic acid (VPA)–induced mouse model of autism. In addition, pentylenetetrazole (PTZ)-induced seizure was significantly attenuated by NaPB treatment in C57BL/6J and BTBR mice. These findings suggest that NaPB may provide a novel therapeutic approach for the treatment of patients with ASD.

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Funding

This work was supported by the KRIBB Research Initiative Program of the Republic of Korea, by the Development of Platform Technology for Innovative Medical Measurements Program (KRISS-2020-GP2020-0004) from the Korea Research Institute of Standards and Science, by the Brain Research Program (NRF-2015M3C7A1029113) and the Bio & Medical Technology Development Program (2019M3A9F3065867 to C-HL) of the National Research Foundation (NRF) funded by the Ministry of Science and ICT of Korea.

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Authors and Affiliations

  1. Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Gwahak-ro 125, Yuseong-gu, Daejeon, 34141, Republic of Korea

    Young-Kyoung Ryu, Hye-Yeon Park, Jun Go, Dong-Hee Choi, Young-Keun Choi, Chul-Ho Lee & Kyoung-Shim Kim

  2. College of Biosciences & Biotechnology, Chung-Nam National University, Daejeon, 34134, Republic of Korea

    Young-Kyoung Ryu & Myungchull Rhee

  3. Department of Brain & Cognitive Sciences, Ewha Womans University, Seoul, 03760, Republic of Korea

    Hye-Yeon Park

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  1. Young-Kyoung Ryu
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Contributions

Author contributions: YK Ryu, CH Lee, and KS Kim designed research; YK Ryu, HY Park, J Go, DH Choi, and YK Choi performed research; DH Choi and YK Choi contributed new reagents/analytic tools; YK Ryu, HY Park, J Go, M Rhee, and KS Kim analyzed data; and YK Ryu, CH Lee, and KS Kim wrote the paper.

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Correspondence to Chul-Ho Lee or Kyoung-Shim Kim.

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All animal experiments were approved by the Institutional Animal Use and Care Committee of the Korea Research Institute of Bioscience and Biotechnology and mouse care and use was in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals (protocol number KRIBB-AEC-18014).

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Ryu, YK., Park, HY., Go, J. et al. Sodium phenylbutyrate reduces repetitive self-grooming behavior and rescues social and cognitive deficits in mouse models of autism. Psychopharmacology 238, 1833–1845 (2021). https://doi.org/10.1007/s00213-021-05812-z

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